Accepted Manuscript Thyroid screening in pregnancy debate Brian Casey, MD Margarita de Veciana, MS, MD PII:
S0002-9378(14)00844-8
DOI:
10.1016/j.ajog.2014.08.013
Reference:
YMOB 9999
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 13 August 2014 Accepted Date: 13 August 2014
Please cite this article as: Casey B, de Veciana M, Thyroid screening in pregnancy debate, American Journal of Obstetrics and Gynecology (2014), doi: 10.1016/j.ajog.2014.08.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
TITLE: THYROID SCREENING IN PREGNANCY DEBATE Selected for inclusion in the SMFM edition of the American Journal of OBGYN
SC
M AN U
Brian Casey, MD Professor, Obstetrics and Gynecology Director, Division Maternal-Fetal Medicine University of Texas Southwestern Medical Center 5323 Harry Hines Blvd. Dallas, Texas 75390-9032
RI PT
AUTHORS:
Phone: 214-648-4746 Fax: 214-648-4763 Email: [email protected]
EP
TE D
Margarita de Veciana, MS, MD Professor, Obstetrics and Gynecology Director, Diabetes in Pregnancy Program Eastern Virginia Medical School Division Maternal-Fetal Medicine Department, Obstetrics and Gynecology 825 Fairfax Avenue, Suite 310 Norfolk VA 23507
AC C
Phone: 757-689-5104 FAX: 757-689-2717 Email: [email protected]
The authors report no conflicts of interest Presented in part at the 33rd annual meeting of the Society for Maternal-Fetal Medicine, San Francisco, CA, Feb. 11-16, 2013.
ACCEPTED MANUSCRIPT
[NOTE TO PRODUCTION: Abstract to appear online only]
INTRODUCTION
RI PT
For more than a decade, endocrinologists and obstetricians have been debating whether screening for thyroid disorders during pregnancy should be routine or
should continue to be based on symptoms and risk factors. The primary impetus
SC
behind this debate was the publication of two observational studies in 1999. (1,2) Both demonstrated that offspring of women with asymptomatic thyroid dysfunction
M AN U
were at increased risk for impaired neurodevelopment. Subsequent reports also indicate that pregnant women with subclinical thyroid disease, particularly those identified with an elevated TSH, may be at increased risk for pregnancy complications like fetal death, preterm birth, or placental abruption. (3,4) These
TE D
data have prompted both obstetric and endocrinologic professional societies to draft statements or recommendations regarding screening for thyroid disease during pregnancy, which are not entirely consistent. (5,6) (7)
EP
This topic was recently debated at the 33rd annual meeting of the SMFM.
AC C
FOR UNIVERSAL THYROID SCREENING The list of patient profiles recommended for targeted thyroid screening in the Endocrine Society Practice Guidelines is very comprehensive and includes all women over 30 years old, patients with clinical symptoms suggestive of thyroid hypofunction, patients with a family history of thyroid disease or autoimmune disorders, personal history of infertility, prior miscarriage, preterm delivery, type 1 diabetes, an autoimmune disorder, goiter or thyroid nodule. Any woman with
ACCEPTED MANUSCRIPT
known anti-thyroid peroxidase antibodies, prior thyroid surgery, or history of radiation to her head and neck region should also be screened. (7) In many clinical practices, few patients would escape screening if the above criteria for screening
RI PT
during pregnancy were followed.
An aggressive case-finding approach is known to miss a considerable proportion of
SC
patients with hypothyroidism. If we screen only women with symptoms of
hypothyroidism during pregnancy, it is important to acknowledge that such
M AN U
symptoms may mimic pregnancy (e.g. weight gain, exhaustion, forgetfulness, dry skin, coarse hair, constipation). This makes this approach to screening less than ideal. Moreover, it has been estimated that only 30-80% of women with hypothyroidism would be identified through screening based on symptoms/risk
TE D
factors. (8,9). (10) (11) Thus, it appears that case finding guidelines are inadequate for identifying all women with thyroid dysfunction.
EP
If a disease is frequent enough and interventions can improve perinatal outcome,
AC C
then screening is usually justified and will likely to be cost-effective. Thyroid dysfunction is the second most common endocrine disorder affecting women of reproductive age (5). (3). A recent national study of over a half-million serum samples from pregnant women included in the Quest Diagnostic Informatics Data Warehouse revealed that of 23% of women that underwent TSH analysis, 15.5% had an elevated TSH. The authors concluded that gestational hypothyroidism is more common than generally acknowledged. (12)
ACCEPTED MANUSCRIPT
Since there are no large randomized trials demonstrating a benefit to routine screening during pregnancy, published cost-effectiveness studies include theoretical
RI PT
models based on the observational study by Haddow and colleagues in 1999. (1) For example, Thung et al published a decision analysis comparing the cost-effectiveness of routine screening versus a case-finding approach. (13) Assuming a 2/3 reduction
SC
in offspring with an IQ < 85 through identification and treatment, this model
predicted routine screening would result in fewer children born with low IQ and
M AN U
save 8.3 million dollars per 100,000 women screened. Similar findings were noted in a Markov model constructed by Dosiou et al. (14)
The million dollar question is whether treatment of patients, particularly those
TE D
identified with subclinical hypothyroidism, makes a difference in perinatal outcome for mom and baby? The association between adverse pregnancy and possible subsequent childhood neuropsychological and cognitive impairment in mothers’
EP
known to have overt hypothyroidism is not questioned. Thyroxine replacement with
AC C
careful monitoring of thyroid function in these women is clearly indicated. (15,16) The problem is that we have conflicting data that thyroid replacement benefits pregnant women identified with milder thyroid dysfunction and their offspring. Several observational studies have suggested a benefit to screening and treatment. (17,18) (19) Conversely, the larger Controlled Antenatal Thyroid Screening (CATS) Trial, revealed that thyroxine replacement in women with isolated high TSH or isolated low fT4 levels had no impact on cognitive function in children evaluated at
ACCEPTED MANUSCRIPT
3 years of age. (20) Although this data appears to be a compelling argument against screening and treatment of pregnant patients with subclinical hypothyroidism, it is important to note that patients in this study did not initiate thyroid replacement
RI PT
therapy until almost 14 weeks gestation—beyond the critical period in fetal brain development
SC
Finally, although the proponent for screening concedes that current evidence does not necessarily justify screening all pregnant women for subclinical hypothyroidism,
M AN U
the benefits of identifying and treating women with overt hypothyroidism are less controversial. Best estimates of the incidence of overt hypothyroidism in the U.S. are on the order of 2 in 1,000. (21) A substantial proportion of these women will not exhibit symptoms of hypothyroidism in the early stages of disease. If we were to
TE D
assume that 50% of these patients might be identified through a case-finding approach, then 1 in 1,000 pregnant women would remain undiagnosed. Said another way, there are roughly 4,000 pregnant women with overt hypothyroidism
EP
who are undiagnosed in the U.S. each year. (22) We currently screen pregnant
AC C
women and neonates for conditions with lower incidence rates. Even if screening for hypothyroidism does not strictly fulfill all criteria for an “ideal” screening test, it is difficult to justify missing this important diagnosis given the beneficial effects treatment may have on both maternal and neonatal outcome.
AGAINST UNIVERSAL THYROID SCREENING
ACCEPTED MANUSCRIPT
The US Preventative Services Task Force has suggested criteria to be met before adopting a new population screen. These criteria include: the diagnosis you are screening for should be prevalent or important enough to warrant population
RI PT
screening; there should be clear evidence of bad outcomes associated with the diagnosis; there should be an intervention which shows improvements in the
SC
outcome; and the screen should be cost effective. (23)
The prevalence of overt thyroid disease is estimated to be 1-3 per 1000 pregnancies
M AN U
and has not historically been considered high enough to justify routine screening. More recently however, lower TSH thresholds (> 2.5 mU/L) for the diagnosis of hypothyroidism have been promoted and women with subclinical thyroid dysfunction are commonly included in estimates of thyroid disease during
TE D
pregnancy. Finally, based largely on the findings from one study of euthyroid pregnant women with thyroid peroxidase antibodies, routine assessment of thyroid autoimmunity has also been suggested. (19) If these subgroups of women were
EP
included to more broadly define hypothyroidism during pregnancy, then the
AC C
prevalence of disease in the U.S. might exceed 5 percent. While this exaggerated prevalence rate alone would seem to justify screening, it does include a majority of women without clear evidence of associated poor outcomes.
Impaired neurodevelopment in offspring is one outcome that is commonly linked to pregnant women with subclinical thyroid disease. Assessment of this evidence is hampered by the fact that two distinct laboratory entities (isolated elevated TSH
ACCEPTED MANUSCRIPT
and isolated low fT4) are often considered together as subclinical hypothyroidism. In 1999, Haddow and colleagues reported that offspring of women with TSH levels greater than the 98th percentile were more likely to have lower IQ scores at 7-9
RI PT
years of age. (1) Even though at least two-thirds of these women had what would be considered overt hypothyroidism, this study is often mistakenly used to link subclinical hypothyroidism with low IQ in offspring. Also, in 1999, Pop and
SC
colleagues reported a link between isolated maternal hypothyroxinemia and lower Bayley scores in children up to 3 years of age. (2, 24) Importantly though,
start with evaluation TSH alone.
M AN U
identifying such women would be unlikely since most thyroid screening regimens
The most compelling current evidence on this issue is the recently completed CATS
TE D
Trial. (20) After screening almost 22,000 pregnant women for either isolated high TSH or isolated low fT4, 390 children of treated women with either diagnosis were compared to 404 children of similar women that were not treated during
EP
pregnancy. Treatment had no effect on mean offspring IQ at age three or the
AC C
number of children with IQ less than 85. The authors of this definitive study concluded that antenatal screening and maternal treatment for women with subclinical thyroid dysfunction did not result in improved cognitive function in children at 3 years of age.
The impact of these diagnoses on pregnancy outcomes represents a second motivating factor behind recommendations for routine screening. However, data
ACCEPTED MANUSCRIPT
linking subclinical thyroid dysfunction to poor pregnancy outcomes are also not consistent. Women with an isolated elevated TSH or subclinical hypothyroidism identified in the first half of pregnancy have been shown to have an increased risk
RI PT
for preterm birth and placental abruption in one study of more than 17, 000 women. (3) However, these findings were not replicated in another large study of over
10,000 women screened in the first or second trimester. (26) Conflicting findings
SC
have also been reported in pregnancies complicated by isolated maternal
hypothyroxinemia. In an analysis of sera from the FaSTER study, there was a weak
M AN U
association between low fT4 during the first or second trimester and the diagnosis of gestational diabetes and birth weight greater than 4000 grams. (26) Conversely, Casey and colleagues were unable to detect any pregnancy outcomes associated with isolated hypothyroxinemia in their larger cohort study. (27) There are
TE D
currently no intervention trials that demonstrate improved outcomes in women with either subclinical hypothyroidism or isolated maternal hypothyroxinemia.
EP
In summary, without the inclusion of women with subclinical thyroid dysfunction,
AC C
the prevalence of women with undetected overt hypothyroidism simply does not justify routine screening. There is an ongoing treatment trial by the Eunice Kennedy-Shriver National Institute of Child Health and Human Development’s Maternal-Fetal Medicine Units Network which will provide further clarity to this important question.
ACCEPTED MANUSCRIPT
REFERENCES: 1.
Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O’Heir CE, Mitchell ML, Hermos RJ, Waisbren SE, Faix JD, Klein RZ. Maternal thyroid
RI PT
deficiency during pregnancy and subsequent neurophysiological development of the child. N Eng J Med 1999;341:549-555. 2.
Pop VJ, Kuijpens JL, van Barr AL, Verkerk G, van Son MM, Vijlder JJ et al. Low
SC
maternal free thyroxine concentrations during early pregnancy are associated
1999;50(2):149-155. 3.
M AN U
with impaired psychomotor development in infancy. Clin Endocrinol (Oxf)
Casey BM, Dashe JS, Wells CE, McIntire DD, Byrd W, Leveno KJ, Cunningham FG. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005;105(2):239-245.
Allan WC, Haddow JE, Palomaki GE, Williams JR, Mitchell ML, Hermos RJ, Faix
TE D
4.
JD, Klein RZ. Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen 2000;7:127-130. ACOG Practice Bulletin 37, Thyroid Disease in Pregnancy., Obstet Gynecol
EP
5.
6.
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2002;100(2):387-396. (reaffirmed in 2010) Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI et al. Clinical Practice Guidelines for Hypothyroidism in Adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid 2012;22(12):1200-1235. 7.
De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, Eastman CJ, Lazarus JH, Luton D, Mandel SJ, Mestman J, Rovet J, Sullivan S.
ACCEPTED MANUSCRIPT
Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab Aug 2012;97(8):2543-2565. Vila L, Velasco I, González S, Morales F, Sánchez E, Lailla JM et al. Detection of
RI PT
8.
thyroid dysfunction in pregnant women; universal screening is justified. Endocrinol Nutr 2012;59:547-560.
Vaidya B, Anthony S, Bilous M, Shields B, Drury J, Hutchison S et al. Detection of
SC
9.
thyroid dysfunction in early pregnancy: universal screening or targeted high
M AN U
risk case finding? Journal Endocrinology and Metabolism 2007;92:203-207. 10. Horacek J, Spitalnikova S, Dlabalova B, Malirova E, Vizda J, Svilias I et al. Universal screening detects two-times more thyroid disorders in early pregnancy than targeted high-risk case finding. Eur J Endocrinol
TE D
2010;163(4):645-650.
11. Chang DLF, Leung AM, Braverman LE. Thyroid Testing during Pregnancy at an Academic Boston Area Medical Center. J Clin Endocrinol Metab
EP
2011;96:E1452-E1456.
AC C
12. Blatt AM, Nakamoto JM, Kaufman HW. National Status of Testing for Hypothyroidism during Pregnancy and Postpartum. J Clin Endocrinol Metab 2012;97(3):777-784. 13. Thung SF, Funai EF, Grobman WA. The cost-effectiveness of universal screening in pregnancy for subclinical hypothyroidism. Am J Obstet Gynecol 2009;200(3):267.e1-7.
ACCEPTED MANUSCRIPT
14. Dosiou C, Sanders GD, Araki SS, Crapo LM. Screening pregnant women for autoimmune thyroid disease: a cost-effectiveness analysis. Eur J Endocrinol 2008;158:841-851.
RI PT
15. Burman KD Gestational hypothyroidism – a need for universal screening? Nat Rev Endocrinol 2012;8:260-261.
16. Stagnaro-Green A, Abalovich M, Alexander E et al Guidelines of the American
SC
Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011;21:1081-1125.
2011;21:1053-1055.
M AN U
17. Teng W, Shan Z. Pregnancy and Thyroid Diseases in China. Thyroid
18. Li Y, Shan Z, Teng W, Yu X, Li Y, Fan C et al. Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their
TE D
children at 25-30 months. Clin Endocrinol 2010;72;825-829. 19. Negro R, Formoso G, Mangieri T, Pezzarossa A, Sazzi D, Hassan H. Levothyroxine treatment in euthyroid pregnant women with autoimmune
EP
thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab
AC C
2006;91:2587-2591.
20. Lazarus JH, Bestwick JP, Channon S, Paradice R, Maina A, Rees R et al. Antenatal Thyroid Screening and Childhood Cognitive Function. N Eng J Med 2012;366:493-501. 21. Casey BM, Leveno KJ. Thyroid disease in pregnancy. Obstet Gynecol 2006;108:1283-1292.
ACCEPTED MANUSCRIPT
22. Klein TA. Thyroid Dysfunction in Pregnancy: The Basic Science and Clinical Evidence Surrounding the Controversy in Management. Letter to the Editor. Obstet Gynecol 2009;113(6):1372.
RI PT
23. US Preventive Task Force Reference. Agency for Healthcare Research and Quality. U. S Preventative Services Task Force Procedure Manual. AHRQ Publication No. 08-05118-EF, July 2008, page 93.
SC
24. Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, de Vijlder JJ.
Maternal hypothyroxinaemia during early pregnancy and subsequent child
M AN U
development: a 3-year follow-up study. Clin Endocrinol (Oxf). 2003;59(3):2828.
25. Behrooz HG, Tohidi M, Mehrabi Y, Behrooz, EG, Tehranidoost M, Azizi F. Subclinical hypothyroidism in pregnancy: intellectual development of
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offspring. Thyroid 2011;21(10):1143-47. 26. Cleary-Goldman, Jane MD; Malone, Fergal D. MD; Lambert-Messerlian, Geralyn PhD; Sullivan, Lisa PhD; Canick, Jacob PhD; Porter, T Flint MD; Luthy, David
EP
MD; Gross, Susan MD; Bianchi, Diana W. MD; D'Alton, Mary E. MD; for the
AC C
FASTER Consortium. Maternal Thyroid Hypofunction and Pregnancy Outcome. Obstet Gynecol 2008;112 (1): 85-92 27. Casey, BM, Dashe JS, Spong CY, McIntire DD, Leveno KJ, Cunningham GF. Perinatal significance of isolated maternal hypothyroxinemia identified in the first half of pregnancy. Obstet Gynecol 2007;109(5):1129-35.
ACCEPTED MANUSCRIPT
28. Abbassi-Ghanavati M, Casey BM, Spong CY, McIntire DD, Halvorson LM, Cunningham FG. Pregnancy outcomes in women with thyroid peroxidase
AC C
EP
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M AN U
SC
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antibodies. Obstetrics & Gynecology. 2010;116(2 Pt 1):381-6, 2010.
S0002-9378(14)00844-8
DOI:
10.1016/j.ajog.2014.08.013
Reference:
YMOB 9999
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 13 August 2014 Accepted Date: 13 August 2014
Please cite this article as: Casey B, de Veciana M, Thyroid screening in pregnancy debate, American Journal of Obstetrics and Gynecology (2014), doi: 10.1016/j.ajog.2014.08.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
TITLE: THYROID SCREENING IN PREGNANCY DEBATE Selected for inclusion in the SMFM edition of the American Journal of OBGYN
SC
M AN U
Brian Casey, MD Professor, Obstetrics and Gynecology Director, Division Maternal-Fetal Medicine University of Texas Southwestern Medical Center 5323 Harry Hines Blvd. Dallas, Texas 75390-9032
RI PT
AUTHORS:
Phone: 214-648-4746 Fax: 214-648-4763 Email: [email protected]
EP
TE D
Margarita de Veciana, MS, MD Professor, Obstetrics and Gynecology Director, Diabetes in Pregnancy Program Eastern Virginia Medical School Division Maternal-Fetal Medicine Department, Obstetrics and Gynecology 825 Fairfax Avenue, Suite 310 Norfolk VA 23507
AC C
Phone: 757-689-5104 FAX: 757-689-2717 Email: [email protected]
The authors report no conflicts of interest Presented in part at the 33rd annual meeting of the Society for Maternal-Fetal Medicine, San Francisco, CA, Feb. 11-16, 2013.
ACCEPTED MANUSCRIPT
[NOTE TO PRODUCTION: Abstract to appear online only]
INTRODUCTION
RI PT
For more than a decade, endocrinologists and obstetricians have been debating whether screening for thyroid disorders during pregnancy should be routine or
should continue to be based on symptoms and risk factors. The primary impetus
SC
behind this debate was the publication of two observational studies in 1999. (1,2) Both demonstrated that offspring of women with asymptomatic thyroid dysfunction
M AN U
were at increased risk for impaired neurodevelopment. Subsequent reports also indicate that pregnant women with subclinical thyroid disease, particularly those identified with an elevated TSH, may be at increased risk for pregnancy complications like fetal death, preterm birth, or placental abruption. (3,4) These
TE D
data have prompted both obstetric and endocrinologic professional societies to draft statements or recommendations regarding screening for thyroid disease during pregnancy, which are not entirely consistent. (5,6) (7)
EP
This topic was recently debated at the 33rd annual meeting of the SMFM.
AC C
FOR UNIVERSAL THYROID SCREENING The list of patient profiles recommended for targeted thyroid screening in the Endocrine Society Practice Guidelines is very comprehensive and includes all women over 30 years old, patients with clinical symptoms suggestive of thyroid hypofunction, patients with a family history of thyroid disease or autoimmune disorders, personal history of infertility, prior miscarriage, preterm delivery, type 1 diabetes, an autoimmune disorder, goiter or thyroid nodule. Any woman with
ACCEPTED MANUSCRIPT
known anti-thyroid peroxidase antibodies, prior thyroid surgery, or history of radiation to her head and neck region should also be screened. (7) In many clinical practices, few patients would escape screening if the above criteria for screening
RI PT
during pregnancy were followed.
An aggressive case-finding approach is known to miss a considerable proportion of
SC
patients with hypothyroidism. If we screen only women with symptoms of
hypothyroidism during pregnancy, it is important to acknowledge that such
M AN U
symptoms may mimic pregnancy (e.g. weight gain, exhaustion, forgetfulness, dry skin, coarse hair, constipation). This makes this approach to screening less than ideal. Moreover, it has been estimated that only 30-80% of women with hypothyroidism would be identified through screening based on symptoms/risk
TE D
factors. (8,9). (10) (11) Thus, it appears that case finding guidelines are inadequate for identifying all women with thyroid dysfunction.
EP
If a disease is frequent enough and interventions can improve perinatal outcome,
AC C
then screening is usually justified and will likely to be cost-effective. Thyroid dysfunction is the second most common endocrine disorder affecting women of reproductive age (5). (3). A recent national study of over a half-million serum samples from pregnant women included in the Quest Diagnostic Informatics Data Warehouse revealed that of 23% of women that underwent TSH analysis, 15.5% had an elevated TSH. The authors concluded that gestational hypothyroidism is more common than generally acknowledged. (12)
ACCEPTED MANUSCRIPT
Since there are no large randomized trials demonstrating a benefit to routine screening during pregnancy, published cost-effectiveness studies include theoretical
RI PT
models based on the observational study by Haddow and colleagues in 1999. (1) For example, Thung et al published a decision analysis comparing the cost-effectiveness of routine screening versus a case-finding approach. (13) Assuming a 2/3 reduction
SC
in offspring with an IQ < 85 through identification and treatment, this model
predicted routine screening would result in fewer children born with low IQ and
M AN U
save 8.3 million dollars per 100,000 women screened. Similar findings were noted in a Markov model constructed by Dosiou et al. (14)
The million dollar question is whether treatment of patients, particularly those
TE D
identified with subclinical hypothyroidism, makes a difference in perinatal outcome for mom and baby? The association between adverse pregnancy and possible subsequent childhood neuropsychological and cognitive impairment in mothers’
EP
known to have overt hypothyroidism is not questioned. Thyroxine replacement with
AC C
careful monitoring of thyroid function in these women is clearly indicated. (15,16) The problem is that we have conflicting data that thyroid replacement benefits pregnant women identified with milder thyroid dysfunction and their offspring. Several observational studies have suggested a benefit to screening and treatment. (17,18) (19) Conversely, the larger Controlled Antenatal Thyroid Screening (CATS) Trial, revealed that thyroxine replacement in women with isolated high TSH or isolated low fT4 levels had no impact on cognitive function in children evaluated at
ACCEPTED MANUSCRIPT
3 years of age. (20) Although this data appears to be a compelling argument against screening and treatment of pregnant patients with subclinical hypothyroidism, it is important to note that patients in this study did not initiate thyroid replacement
RI PT
therapy until almost 14 weeks gestation—beyond the critical period in fetal brain development
SC
Finally, although the proponent for screening concedes that current evidence does not necessarily justify screening all pregnant women for subclinical hypothyroidism,
M AN U
the benefits of identifying and treating women with overt hypothyroidism are less controversial. Best estimates of the incidence of overt hypothyroidism in the U.S. are on the order of 2 in 1,000. (21) A substantial proportion of these women will not exhibit symptoms of hypothyroidism in the early stages of disease. If we were to
TE D
assume that 50% of these patients might be identified through a case-finding approach, then 1 in 1,000 pregnant women would remain undiagnosed. Said another way, there are roughly 4,000 pregnant women with overt hypothyroidism
EP
who are undiagnosed in the U.S. each year. (22) We currently screen pregnant
AC C
women and neonates for conditions with lower incidence rates. Even if screening for hypothyroidism does not strictly fulfill all criteria for an “ideal” screening test, it is difficult to justify missing this important diagnosis given the beneficial effects treatment may have on both maternal and neonatal outcome.
AGAINST UNIVERSAL THYROID SCREENING
ACCEPTED MANUSCRIPT
The US Preventative Services Task Force has suggested criteria to be met before adopting a new population screen. These criteria include: the diagnosis you are screening for should be prevalent or important enough to warrant population
RI PT
screening; there should be clear evidence of bad outcomes associated with the diagnosis; there should be an intervention which shows improvements in the
SC
outcome; and the screen should be cost effective. (23)
The prevalence of overt thyroid disease is estimated to be 1-3 per 1000 pregnancies
M AN U
and has not historically been considered high enough to justify routine screening. More recently however, lower TSH thresholds (> 2.5 mU/L) for the diagnosis of hypothyroidism have been promoted and women with subclinical thyroid dysfunction are commonly included in estimates of thyroid disease during
TE D
pregnancy. Finally, based largely on the findings from one study of euthyroid pregnant women with thyroid peroxidase antibodies, routine assessment of thyroid autoimmunity has also been suggested. (19) If these subgroups of women were
EP
included to more broadly define hypothyroidism during pregnancy, then the
AC C
prevalence of disease in the U.S. might exceed 5 percent. While this exaggerated prevalence rate alone would seem to justify screening, it does include a majority of women without clear evidence of associated poor outcomes.
Impaired neurodevelopment in offspring is one outcome that is commonly linked to pregnant women with subclinical thyroid disease. Assessment of this evidence is hampered by the fact that two distinct laboratory entities (isolated elevated TSH
ACCEPTED MANUSCRIPT
and isolated low fT4) are often considered together as subclinical hypothyroidism. In 1999, Haddow and colleagues reported that offspring of women with TSH levels greater than the 98th percentile were more likely to have lower IQ scores at 7-9
RI PT
years of age. (1) Even though at least two-thirds of these women had what would be considered overt hypothyroidism, this study is often mistakenly used to link subclinical hypothyroidism with low IQ in offspring. Also, in 1999, Pop and
SC
colleagues reported a link between isolated maternal hypothyroxinemia and lower Bayley scores in children up to 3 years of age. (2, 24) Importantly though,
start with evaluation TSH alone.
M AN U
identifying such women would be unlikely since most thyroid screening regimens
The most compelling current evidence on this issue is the recently completed CATS
TE D
Trial. (20) After screening almost 22,000 pregnant women for either isolated high TSH or isolated low fT4, 390 children of treated women with either diagnosis were compared to 404 children of similar women that were not treated during
EP
pregnancy. Treatment had no effect on mean offspring IQ at age three or the
AC C
number of children with IQ less than 85. The authors of this definitive study concluded that antenatal screening and maternal treatment for women with subclinical thyroid dysfunction did not result in improved cognitive function in children at 3 years of age.
The impact of these diagnoses on pregnancy outcomes represents a second motivating factor behind recommendations for routine screening. However, data
ACCEPTED MANUSCRIPT
linking subclinical thyroid dysfunction to poor pregnancy outcomes are also not consistent. Women with an isolated elevated TSH or subclinical hypothyroidism identified in the first half of pregnancy have been shown to have an increased risk
RI PT
for preterm birth and placental abruption in one study of more than 17, 000 women. (3) However, these findings were not replicated in another large study of over
10,000 women screened in the first or second trimester. (26) Conflicting findings
SC
have also been reported in pregnancies complicated by isolated maternal
hypothyroxinemia. In an analysis of sera from the FaSTER study, there was a weak
M AN U
association between low fT4 during the first or second trimester and the diagnosis of gestational diabetes and birth weight greater than 4000 grams. (26) Conversely, Casey and colleagues were unable to detect any pregnancy outcomes associated with isolated hypothyroxinemia in their larger cohort study. (27) There are
TE D
currently no intervention trials that demonstrate improved outcomes in women with either subclinical hypothyroidism or isolated maternal hypothyroxinemia.
EP
In summary, without the inclusion of women with subclinical thyroid dysfunction,
AC C
the prevalence of women with undetected overt hypothyroidism simply does not justify routine screening. There is an ongoing treatment trial by the Eunice Kennedy-Shriver National Institute of Child Health and Human Development’s Maternal-Fetal Medicine Units Network which will provide further clarity to this important question.
ACCEPTED MANUSCRIPT
REFERENCES: 1.
Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O’Heir CE, Mitchell ML, Hermos RJ, Waisbren SE, Faix JD, Klein RZ. Maternal thyroid
RI PT
deficiency during pregnancy and subsequent neurophysiological development of the child. N Eng J Med 1999;341:549-555. 2.
Pop VJ, Kuijpens JL, van Barr AL, Verkerk G, van Son MM, Vijlder JJ et al. Low
SC
maternal free thyroxine concentrations during early pregnancy are associated
1999;50(2):149-155. 3.
M AN U
with impaired psychomotor development in infancy. Clin Endocrinol (Oxf)
Casey BM, Dashe JS, Wells CE, McIntire DD, Byrd W, Leveno KJ, Cunningham FG. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005;105(2):239-245.
Allan WC, Haddow JE, Palomaki GE, Williams JR, Mitchell ML, Hermos RJ, Faix
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4.
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